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Home , Appetite, Histamine, Insomnia, Lithium (medication), Mirtazapine, Parosmia

Suicidality and increased the risk compared to of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of REMERON® () Tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. and certain other psychiatric disorders are themselves associated with increases in the risk of . Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. REMERON is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use)

DESCRIPTION REMERON® (mirtazapine) Tablets are an orally administered . Mirtazapine has a tetra-cyclic chemical structure and belongs to the piperazino-azepine group of compounds. It is designated 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] benzazepine and has the empirical formula of C17H19N3. Its molecular weight is 265.36. The structural formula is the following and it is the :

Mirtazapine is a white to creamy white crystalline powder which is slightly soluble in . REMERON is supplied for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine, and unscored film-coated tablets containing 45 mg of mirtazapine. Each also contains corn starch, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose, and other inactive ingredients.

CLINICAL The of REMERON® (mirtazapine) Tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown.

1 Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic α2 inhibitory and , an action that is postulated to result in an increase in central noradrenergic and serotonergic activity.

Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors.

Mirtazapine is a potent antagonist of (H1) receptors, a property that may explain its prominent effects.

Mirtazapine is a moderate peripheral α1 , a property that may explain the occasional orthostatic reported in association with its use. Mirtazapine is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of side effects associated with its use. REMERON (mirtazapine) Tablets are rapidly and completely absorbed following oral administration and have a half-life of about 20 to 40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of in the has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment. Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and followed by glucuronide conjugation. In vitro data from microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8­ hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute of about 50%. It is eliminated predominantly via (75%) with 15% in . Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (–) has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer. Plasma levels are linearly related to dose over a dose range of 15 to 80 mg. The mean elimination half- life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5). Mirtazapine is approximately 85% bound to plasma over a concentration range of 0.01 to 10 mcg/mL. Special Populations Geriatric Following oral administration of REMERON (mirtazapine) Tablets 20 mg/day for 7 days to subjects of varying ages (range, 25–74), oral of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering REMERON to elderly patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

2 Pediatrics Safety and effectiveness of mirtazapine in the pediatric population have not been established (see PRECAUTIONS). Gender The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) (see Pharmacokinetics). Race There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of REMERON. Renal Insufficiency The disposition of mirtazapine was studied in patients with varying degrees of renal function. Elimination of mirtazapine is correlated with creatinine clearance. Total body clearance of mirtazapine was reduced approximately 30% in patients with moderate (Clcr = 11–39 mL/min/1.73 m2) and approximately 50% in patients with severe (Clcr = <10 mL/min/1.73 m2) renal impairment when compared to normal subjects. Caution is indicated in administering REMERON to patients with compromised renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Hepatic Insufficiency Following a single 15-mg oral dose of REMERON, the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering REMERON to patients with compromised hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Clinical Trials Showing Effectiveness The efficacy of REMERON (mirtazapine) Tablets as a treatment for major depressive disorder was established in 4 placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from a dose range of 5 mg up to 35 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of mirtazapine over placebo was also found for certain factors of the HDRS, including /somatization factor and disturbance factor. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21 to 32 mg/day. A fifth study of similar design utilized a higher dose (up to 50 mg) per day and also showed effectiveness. Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings. In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8 to 12 weeks of treatment on REMERON were randomized to continuation of REMERON or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤8 and a CGI-Improvement

3 score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8 to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued REMERON treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients.

INDICATIONS AND USAGE REMERON® (mirtazapine) Tablets are indicated for the treatment of major depressive disorder. The efficacy of REMERON in the treatment of major depressive disorder was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the Diagnostic and Statistical Manual of Mental Disorders – 3rd edition (DSM-III) category of major depressive disorder (see CLINICAL PHARMACOLOGY). A (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or , or , or retardation, increased , feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or . The effectiveness of REMERON in hospitalized depressed patients has not been adequately studied. The efficacy of REMERON in maintaining a response in patients with major depressive disorder for up to 40 weeks following 8 to 12 weeks of initial open-label treatment was demonstrated in a placebo- controlled trial. Nevertheless, the physician who elects to use REMERON for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS Hypersensitivity REMERON® (mirtazapine) Tablets are contraindicated in patients with a known hypersensitivity to mirtazapine or to any of the excipients.

4 Inhibitors The concomitant use of REMERON Tablets and a monoamine oxidase (MAO) inhibitor is contraindicated. REMERON should not be used within 14 days of initiating or discontinuing therapy with a monoamine oxidase inhibitor (MAOI) (see WARNINGS, PRECAUTIONS: Drug Interactions, and DOSAGE AND ADMINISTRATION).

WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant , and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases

5 No occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, , , aggressiveness, impulsivity, (psychomotor restlessness), , and , have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the , in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for REMERON® (mirtazapine) Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for : A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that REMERON (mirtazapine) Tablets are not approved for use in treating bipolar depression.

Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with REMERON (mirtazapine) Tablets developed [absolute count (ANC)

6 <500/mm3 with associated signs and symptoms, e.g., fever, , etc.] and a third patient developed severe (ANC <500/mm3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All 3 patients recovered after REMERON was stopped. These 3 cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low WBC count, treatment with REMERON should be discontinued and the patient should be closely monitored. MAO Inhibitors In patients receiving other drugs for major depressive disorder in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued a drug for major depressive disorder and then are started on an MAOI, there have been reports of serious and sometimes fatal reactions, including , , , , , , rigidity, diaphoresis, hyperthermia, autonomic instability with rapid fluctuations of vital signs, seizures, and mental status changes ranging from agitation to coma. Although there are no human data pertinent to such an interaction with REMERON (mirtazapine) Tablets, it is recommended that REMERON not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI.

Serotonin Syndrome On rare occasions syndrome has occurred in association with treatment of REMERON Tablets, particularly when given in combination with other serotonergic drugs. As may result in potentially life-threatening conditions, treatment with REMERON should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including , irritability, extreme agitation progressing to and coma, and supportive symptomatic treatment should be initiated. Due to the risk of serotonin syndrome, REMERON should not be used in combination with MAO inhibitors or serotonin-precursors (such as L- and oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (e.g., , , , St. John’s wort, and most antidepressants) (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions).

PRECAUTIONS General

Discontinuation Symptoms There have been reports of adverse reactions upon the discontinuation of REMERON® (mirtazapine) Tablets (particularly when abrupt), including but not limited to the following: dizziness, abnormal , sensory disturbances (including paresthesia and electric sensations), agitation, anxiety,

7 fatigue, confusion, , tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance. The majority of the reported cases are mild and self-limiting. Even though these have been reported as adverse reactions, it should be realized that these symptoms may be related to underlying . Patients currently taking REMERON should NOT discontinue treatment abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue treatment with REMERON, a gradual reduction in the dose, rather than an abrupt cessation, is recommended. Akathisia/Psychomotor Restlessness The use of antidepressants has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental. Hyponatremia Hyponatremia has been reported very rarely with the use of mirtazapine. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatremia. In US controlled studies, somnolence was reported in 54% of patients treated with REMERON (mirtazapine) Tablets, compared to 18% for placebo and 60% for . In these studies, somnolence resulted in discontinuation for 10.4% of REMERON-treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of REMERON. Because of the potentially significant effects of REMERON on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug’s effect on their own psychomotor performance (see Information for Patients). Dizziness In US controlled studies, dizziness was reported in 7% of patients treated with REMERON, compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of REMERON. Increased Appetite/ In US controlled studies, appetite increase was reported in 17% of patients treated with REMERON, compared to 2% for placebo and 6% for amitriptyline. In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON discontinued for weight gain. In an 8-week­ long pediatric of doses between 15 to 45 mg/day, 49% of REMERON-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients (see PRECAUTIONS: Pediatric Use). / In US controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with REMERON, compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting increases to ≥500 mg/dL were observed in

8 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline. Transaminase Elevations Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to REMERON in a pool of short-term US controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the levels returned to normal despite continued REMERON treatment. REMERON should be used with caution in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Activation of Mania/Hypomania Mania/hypomania occurred in approximately 0.2% (3/1299 patients) of REMERON-treated patients in US studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania. Seizure In premarketing clinical trials, only 1 seizure was reported among the 2796 US and non-US patients treated with REMERON. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients. Use in Patients with Concomitant Illness Clinical experience with REMERON in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with or conditions that affect or hemodynamic responses. REMERON has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant disease. REMERON was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. REMERON should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (, , and treatment with antihypertensive medication). Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR) = 11–39 mL/min/1.73 m2] and severe [GFR <10 mL/min/1.73 m2] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering REMERON to such patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). INFORMATION FOR PATIENTS Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with REMERON (mirtazapine) Tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant , Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for REMERON. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

9 Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking REMERON. Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Agranulocytosis Patients who are to receive REMERON should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, ulceration, or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection. Interference with Cognitive and Motor Performance REMERON may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient’s ability to drive, use machines, or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that REMERON therapy does not adversely affect their ability to engage in such activities. Completing Course of Therapy While patients may notice improvement with REMERON therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs, since there is a potential for REMERON to interact with other drugs. The impairment of cognitive and motor skills produced by REMERON has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.

10 Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during REMERON therapy. Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. Laboratory Tests There are no routine laboratory tests recommended.

DRUG INTERACTIONS As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY). Monoamine Oxidase Inhibitors (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.) Serotonergic drugs Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when REMERON Tablets are coadministered with other drugs or agents that may affect the serotonergic systems, such as tryptophan, triptans, , serotonin inhibitors, , lithium, tramadol, or St. John's wort (see CONTRAINDICATIONS and WARNINGS). Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON (mirtazapine) Tablets may be affected by the induction or inhibition of drug-metabolizing . Drugs that are Metabolized by and/or Inhibit Enzymes CYP Enzyme Inducers (these studies used both drugs at steady state) Phenytoin: In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. : In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%. When phenytoin, carbamazepine, or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose. CYP Enzyme Inhibitors : In healthy male patients (n=12), when cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily)

11 at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued. : In healthy, male, Caucasian patients (n=24), coadministration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30-mg dose of mirtazapine by approximately 40% and 50%, respectively. Caution should be exercised when coadministering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or . : In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor.

Other Drug-Drug Interactions Amitriptyline: In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes in the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. Warfarin: In healthy male subjects (n=16), mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalized Ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine, a more pronounced effect can not be excluded. It is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine. Lithium: No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of lithium (600 mg/day for 10 days) at steady state and a single 30 mg dose of mirtazapine. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown. : In an in vivo, nonrandomized, interaction study, subjects (n=6) in need of treatment with an and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg b.i.d.).

Alcohol Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON. Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON.

12 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on an mg/m2 basis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to is not known. The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of REMERON (mirtazapine) Tablets. Mutagenesis Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells. Impairment of Fertility In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [20 times the maximum recommended human dose (MRHD) on an mg/m2 basis]. Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the MRHD, and pre­ implantation losses occurred at 20 times the MRHD. Pregnancy Teratogenic Effects – Pregnancy Category C Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively [20 and 17 times the maximum recommended human dose (MRHD) on an mg/m2 basis, respectively], have revealed no evidence of teratogenic effects. However, in rats, there was an increase in postimplantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. The effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on an mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether mirtazapine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when REMERON (mirtazapine) Tablets are administered to nursing women. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING

13 and WARNINGS: Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with REMERON (mirtazapine) Tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of REMERON in a child or adolescent must balance the potential risks with the clinical need. In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of REMERON- treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for REMERON-treated patients versus 1 kg (2 kg SD) for placebo-treated patients (see PRECAUTIONS: Increased Appetite/Weight Gain). Geriatric Use Approximately 190 elderly individuals (≥65 years of age) participated in clinical studies with REMERON (mirtazapine) Tablets. This drug is known to be substantially excreted by the (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over- in the elderly. No unusual adverse age-related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering REMERON to elderly patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS Associated with Discontinuation of Treatment Approximately 16% of the 453 patients who received REMERON® (mirtazapine) Tablets in US 6­ week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7% of the 361 placebo-treated patients in those studies. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) included:

Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US REMERON Trials Adverse Percentage of Patients Discontinuing with Adverse Event Event REMERON Placebo (n=453) (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0%

Commonly Observed Adverse Events in US Controlled Clinical Trials The most commonly observed adverse events associated with the use of REMERON (mirtazapine) Tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo- treated patients (REMERON incidence at least twice that for placebo) were:

Common Treatment-Emergent Adverse Events Associated with the Use of REMERON in 6-Week US Trials Adverse Percentage of Patients Reporting Adverse Event E

14 REMERON Placebo (n=453) (n=361) Somnolence 54% 18% Increased Appetite 17% 2% Weight Gain 12% 2% Dizziness 7% 3%

15 Adverse Events Occurring at an Incidence of 1% or More Among REMERON-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among REMERON (mirtazapine) Tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. INCIDENCE OF ADVERSE CLINICAL EXPERIENCESa (≥1%) IN SHORT­ TERM US CONTROLLED STUDIES Body System Adverse Clinical REMERON Placebo Experience (n=453) (n=361) Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Somnolence 54% 18% Dizziness 7% 3% Abnormal Dreams 4% 1% Thinking Abnormal 3% 1% Tremor 2% 1% Confusion 2% 0% Respiratory System Dyspnea 1% 0% Urogenital System

16 Urinary Frequency 2% 1% a Events reported by at least 1% of patients treated with REMERON are included, except the following events which had an incidence on placebo greater than or equal to REMERON: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, , flatulence, insomnia, nervousness, decreased, hypertonia, pharyngitis, , sweating, amblyopia, , perversion.

ECG Changes The electrocardiograms for 338 patients who received REMERON (mirtazapine) Tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and –3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown. Other Adverse Events Observed During the Premarketing Evaluation of REMERON During its premarketing assessment, multiple doses of REMERON (mirtazapine) Tablets were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART- based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of REMERON who experienced an event of the type cited on at least 1 occasion while receiving REMERON. All reported events are included except those already listed in the previous table, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote. It is important to emphasize that, although the events reported occurred during treatment with REMERON, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in the previous table appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections. Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal. Cardiovascular System: frequent: , vasodilatation; infrequent: angina pectoris, myocardial

17 infarction, bradycardia, ventricular extrasystoles, syncope, , hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left . Digestive System: frequent: vomiting, ; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, , aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. : rare: goiter, . Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. Metabolic and Nutritional Disorders: frequent: ; infrequent: dehydration, ; rare: , SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, mellitus, hyponatremia. Musculoskeletal System: frequent: myasthenia, ; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, , twitching, agitation, anxiety, , , paresthesia; infrequent: , delirium, , depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, , manic reaction, neurosis, , hostility, increased, emotional lability, , paranoid reaction; rare: aphasia, , akathisia (psychomotor restlessness), stupor, , diplopia, drug dependence, paralysis, grand mal , hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. Respiratory System: frequent: increased, sinusitis; infrequent: epistaxis, bronchitis, , pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup. Skin and Appendages: frequent: pruritus, rash; infrequent: , exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. Special : infrequent: eye pain, abnormality of accommodation, , deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, media, taste loss, parosmia. Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, , vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: , urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. Other Adverse Events Observed During Postmarketing Evaluation of REMERON Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include 4 cases of the ventricular arrhythmia . In 3 of the 4 cases, however, concomitant drugs were implicated. All patients recovered.

18 Cases of severe skin reactions, including Stevens-Johnson Syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported.

DRUG ABUSE AND DEPENDENCE Controlled Substance Class REMERON® (mirtazapine) Tablets are not a controlled substance. Physical and Psychologic Dependence REMERON (mirtazapine) Tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance, or . While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of REMERON misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior). OVERDOSAGE Human Experience There is very limited experience with REMERON® (mirtazapine) Tablets overdose. In premarketing clinical studies, there were 8 reports of REMERON overdose alone or in combination with other pharmacological agents. The only death reported while taking REMERON was in combination with amitriptyline and in a non-US clinical study. Based on plasma levels, the REMERON dose taken was 30 to 45 mg, while plasma levels of amitriptyline and chlorprothixene were found to be at toxic levels. All other premarketing overdose cases resulted in full recovery. reported in association with overdose included disorientation, drowsiness, impaired , and tachycardia. There were no reports of ECG abnormalities, coma, or following overdose with REMERON alone. Overdose Management Treatment should consist of those general measures employed in the management of overdose with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. There is no experience with the use of forced diuresis, , hemoperfusion, or exchange transfusion in the treatment of mirtazapine overdosage. No specific for mirtazapine are known. In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

19 DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for REMERON® (mirtazapine) Tablets is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of REMERON in the treatment of major depressive disorder, the effective dose range was generally 15 to 45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for REMERON has not been adequately explored, patients not responding to the initial 15-mg dose may benefit from dose increases up to a maximum of 45 mg/day. REMERON has an elimination half-life of approximately 20 to 40 hours; therefore, dose changes should not be made at intervals of less than 1 to 2 weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. Elderly and Patients with Renal or Hepatic Impairment The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment (see PRECAUTIONS and CLINICAL PHARMACOLOGY). Maintenance/Extended Treatment It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of REMERON (mirtazapine) Tablets has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8 to 12 weeks of initial treatment at a dose of 15 to 45 mg/day (see CLINICAL PHARMACOLOGY). Based on these limited data, it is unknown whether or not the dose of REMERON needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Switching Patients To or From a Monoamine Oxidase Inhibitor Concomitant use of REMERON (mirtazapine) Tablets with MAOIs is contraindicated. At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with REMERON (mirtazapine) Tablets. In addition, at least 14 days should be allowed after stopping REMERON before starting an MAOI.

Discontinuation of Remeron Treatment Symptoms associated with the discontinuation or dose reduction of REMERON Tablets have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction. A gradual reduction in the dose over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see PRECAUTIONS and ADVERSE REACTIONS).

HOW SUPPLIED

20 REMERON® (mirtazapine) Tablets are supplied as:

T Z 15 mg Tablets — oval, scored, yellow, coated, with “Organon” debossed on 1 side and “ 3 ” on the other side. Bottles of 30 NDC 0052-0105-30 T Z 30 mg Tablets — oval, scored, red-brown, coated, with “Organon” debossed on 1 side and “ 5 ” on the other side. Bottles of 30 NDC 0052-0107-30 T Z 45 mg Tablets — oval, white, coated, with “Organon” debossed on 1 side and “ 7 ” on the other side. Bottles of 30 NDC 0052-0109-30 Storage Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.

only

Manufactured by N.V. Organon, Oss, The . Distributed by Schering Corporation, a subsidiary of Schering-Plough Corporation, Kenilworth, NJ 07033 USA.

© 1996, 2007, Schering Corporation. All rights reserved. Rev. X/XX

21 Medication Guide REMERON® (rĕm' - ĕ – rŏn) Tablets (mirtazapine)

What is the most important information I should know about REMERON®?

Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions

Read the Medication Guide that comes with you or your family member’s antidepressant . This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: • all risks and benefits of treatment with antidepressant medicines • all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.

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• Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What else do I need to know about antidepressant medicines? • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.

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• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

What is REMERON®? REMERON is a prescription medicine used to treat depression.

Who should not take REMERON®? Do not take REMERON if you: • are allergic to mirtazapine or any of the ingredients in REMERON. See the end of the Medication Guide for a complete list of ingredients in REMERON. • currently take or have taken within the last 14 days, any medicine known as Monamine Oxidase inhibitors (MAOI). Taking an MAOI with certain other medicines, with similar actions to REMERON, can cause serious or even life-threatening side effects.

What should I tell my doctor before taking REMERON®? Tell your doctor about all your medical conditions, including if you: • have or had liver problems • have or had kidney problems • have or had manic episodes • have had a seizure (convulsion) • have any heart problems • tend to get dizzy or faint • are pregnant or planning to become pregnant. It is not known if REMERON will harm your unborn baby.

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• are . It is not known if REMERON passes into your milk or if it can harm your unborn baby.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, and herbal supplements. REMERON and some medicines may interact with each other and may not work as well, or cause possible serious side effects. Your doctor can tell you if it is safe to take REMERON with your other medicines.

How should I take REMERON®? • Take REMERON exactly as prescribed by your doctor. • Take REMERON at the same time each day, preferably in the evening at . • Swallow REMERON as directed. • It is common for antidepressant medicines such as REMERON to take up to a few weeks before you start to feel better. Do not stop taking REMERON if you do not feel results right away. • Do not stop taking or change the dose of REMERON without talking to your doctor, even if you feel better. • If you miss a dose of REMERON, do not take another dose to make up for the dose you forgot. Wait and take your tablet at the next regular time. • If you take too much REMERON, call your doctor or poison control center or go to the emergency room right away.

What should I avoid while taking REMERON®? • REMERON can cause drowsiness, which may affect your ability to make decisions, think clearly or react quickly. You should not drive, operate heavy machinery or do other dangerous activities until you know how REMERON affects you. • Avoid drinking alcohol or taking diazepam (a medicine used for anxiety, insomnia and seizures, for example) or similar medicines, while taking REMERON. If you are unsure about whether a certain medication can be taken together with REMERON, please discuss this with your doctor.

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What are the possible side effects of REMERON®?

REMERON may be associated with serious side effects, including: • See the beginning of this Medication Guide- Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions • Serotonin Syndrome: This is a condition that can be life threatening. Call your doctor right away if you become severely ill and have some or all of these symptoms: o stiffness o muscle spasm o confusion o irritability o agitation o increased body temperature o fast heart rate o increased blood pressure

• Decreased White Blood Cells called , which are needed to fight . Tell your doctor if you have any indication of infection such as fever, chills, sore throat, or mouth or nose sores, especially symptoms which are flu-like. • Increased cholesterol and triglyceride levels in your blood • Symptoms when stopping Remeron (discontinuation symptoms). Side effects may occur when stopping Remeron (discontinuation symptoms), especially when therapy is stopped suddenly. Your healthcare provider may want to decrease your dose slowly to help avoid side effects. Some of these side effects may include: o dizziness o abnormal dreams o agitation o anxiety o fatigue o confusion o headache

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o shaking o tingling sensation o nausea o vomiting o sweating • Mania • Seizures • Low levels in your blood: Call your doctor right away if you become severely ill and have some or all of these symptoms: o headache o feel weak o confusion o problems concentrating o memory problems o feel unsteady

The most common side effects with REMERON include: sleepiness, increased appetite, weight gain and dizziness.

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects with REMERON. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REMERON®? • Store at room temperature (77°F). Storage at 59°F to 86°F is permitted occasionally. • Protect from light and moisture.

Keep REMERON® Tablets and all medicines out of the reach of children,

General information about REMERON®

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• Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. • Do not use REMERON for a condition for which it was not prescribed. Do not give REMERON to other people, even if they have the same condition as you have. It may harm them. • This Medication guide summarizes the most important information about REMERON. If you have any concerns or would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about REMERON that is written for health professionals.

For more information, go to www.REMERON.com or call 1-800-526-4099.

What are the ingredients in REMERON® Tablets ? Active ingredient: mirtazapine.

Inactive ingredients:

15mg tablets: Starch (corn), hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose, hypromellose, polyethylene glycol 8000, titanium dioxide, ferric oxide (yellow).

30mg tablets: Starch (corn), hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose, hypromellose, polyethylene glycol 8000, titanium dioxide, ferric oxide (yellow), ferric oxide (red).

45mg tablets: Starch (corn), hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose, hypromellose, polyethylene glycol 8000, titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Issued Month Year

© 2007, 2009, Schering Corporation. All rights reserved.

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Rev.X/XX

Manufactured by: N.V. Organon, Oss, The Netherlands Distributed by Schering Corporation, a subsidiary of Schering-Plough Corporation, Kenilworth, NJ 07033 USA.

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